1,1-dimethyl-2-thio-3-(4-alkyl-piperazino)-thocarbonyl ureas

ABSTRACT

Novel dithiobiurets of one of the following formulas:   AND   WHERE R, R1, R2, and R3 are certain organic radicals, THE RING   CONTAINS 5-8 ATOMS, AND A, E, and G are alkylene, and SALTS OF THESE DITHIOBIURETS. An exemplary compound: 1,1-dimethyl-2-thio-3-((4propylpiperazin-1-yl)-thiocarbonyl)urea.

United States Patent [19] Bellina 1 ,1-DIMETHYL-2-THIO-3-[(4-ALKYL- PIPERAZINO)-THOCARBONYL]UREAS [75] Inventor: Russell F. Bellina, Wilmington, Del.

[73] Assignee: E. l. du Pont de Nemours & Company, Wilmington, Del.

22 Filed: Maya, 1973 [21] Appl. No.: 358,394

52 US. c1.... 260/268 c; 260/239 BC; 260/239 B; 260/250 A; 260/309.7; 260/310; 260/326.83; 260/552 sc; 424/250; 260/247.1 M

51 Int. Cl c070 5/70 [58] Field of Search 260 552 R, 268 c, 268 BC [56] References Cited UNITED STATES PATENTS 2,704,244 3/1955 Goodhue et a]. l 260/552 R 3,166,564 l/l965 Diveley 260/293.63 3,787,490 1/1974 Zielinski 260/552 R Primary Examiner-Donald G. Daus Assistant ExaminerJose Tovar 57 ABSTRACT I Novel dithiobiurets of one of the following formulas:

[ June 1 7, 1975 and where R, R,, R and R are'certain organic radicals,

the ring compound:

l,1-DIMETHYL-2-THIO-3-(4-ALKYL- d is 2 through PlPERAZlNO)-THOCARBONYL UREAS e is l or 2; with the provision that the total number BACKGROUND OF THE INVENTION of atoms the Japanese Pat. application No. 43-54280/1968, pub- 5 A lished Mar. 25, 1971, as Pat. application Publication No. 46-1 1679/1971 discloses a class of dithiobiurets of -N N the general formula l 3 R R is between 5 and 8, inclusive;

N C NH C N R is alkyl ofl through 6 carbon atoms; with the pro- H vision that the sum of carbon atoms in A, E, and R R S S R is not more than 10;

G is where R and R can be hydrogen or lower alkyl and R CH 4 l and R can be hydrogen, lower alkyl, cyanoalkyl, for G is )m or )n myl, acetyl, halogen acetyl, and pyridyl. These compounds are said to be useful as insecticides, housefly antifertility agents, and mite-killing agents.

It has been found, however, that these compounds m is 0 through 6; exhibit undesirable levels of phytotoxIcIty. It IS thIs n is l or 2;

problem that the compounds of the present nvent on R1 is m ethyl, (CH2)2 NR2R3 or (CH2' have overcome. Compounds of the present Invention NR R 3 2 3! provide excellent protection against mites without causing any significant damage to the treated plants. R2 is methyl or ethyl;

R is alkyl of 1 through 6 carbon atoms; SUMMARY OF THE INVENTION 2 and R3 taken together can be H2),.; and

p is 4 through 6; with the provision that the sum of carbon atoms in G, R R and R is not more than 10; and salts of the above compounds with acids or bases, the acids being selected from those having an ionozation 5 constant of at least 1 X 10 and the salts formed with bases containing a cation selected from Li*, Na*, K*, CA, Cu Zn, Mg, Mn, and

This invention is a class of novel miticidal compounds which can be represented by the following formulas:

Che

R R l 6 Ia and 5 CH; S S R R where g g R R and R can be the same or different and each can be hydrogen, alkyl of 1 through 4 carbon CH3 R3 atoms, or hydroxy alkyl of 2 through 4 carbon atoms; and R is hydrogen, alkyl of 1 through 12 carbon atoms, benzyl, amino, methylamino, or di- Ib methylamino; R and R, can be taken together to form a ring that is (CH O-(CH or where: -(Cl-l where j is 4-6 and R and R are H.

A is Examples of such acids include HCl, l-lBr, HF, HI, H 50 HSCN, H PO H 80 acetic acid, oxalic acid, CH3 tartaric acid, benzoic acid, and N-lauryl-N-methyl-2- aminoethane sulfonic acid. (CH2 a: or (CH2) b cH ln addition to the miticidal utility of the compounds of the present invention, they may be used to prepare a is 0 through 4; the class of compounds which comprise the subject b is 1 or 2; matter of copending US. patent application Ser. No. E is 358,395 filed simultaneously herewith by Russell F. Bellina, which compounds are disclosed therein as CH3 being useful for the protection of plants from mites, l fungi, aphids, Colorado potato beetle, Mexican bean ld' or e" 5 beetle, and boll weevil.

For the sake of clarity it is mentioned that while the compounds of the present invention are, in fact, dithiobiurets and are identified generically as such, the various species within the scope of the present invention are identified as thiocarbonyl ureas and thiocarbamoyl ureas in order to permit the orderly and systematic naming of said species.

DETAILED DESCRIPTION OF THE INVENTION Preferred Compounds Certain of the compounds of Formulas Ia and lb are preferred because of their ease of synthesis and higher activity. These compounds include those compounds of Formula la where:

A and E are (Cl-I and R is alkyl of 1 through 4 carbon atoms;

and salts thereof; and those compounds of Formula lb where:

R is methyl;

R is methyl or ethyl;

R is methyl or ethyl;

and salts thereof.

Compounds within this scope that are most preferred include:

1 ,1-dimethyl-2-thio-3-[(4-methylpiperazin-1-yl)- thiocarbonyl]urea sodium salt of l ,1-dimethyl-2-thio-3-[(4- methylpiperazinl -yl )-thiocarbonyl]urea hydrobromic acid salt of 1,l-dimethyl-2-thio-3-[(4- methylpiperazinl -yl )-thiocarbonyl urea 1,1-dimethyl-2-thio-3-[(4-propylpiperazin-l-yl)- thiocarbonyl]urea 1,1-dimethyl-2-thio-3-[N-(Z-dimethylaminoethyl)- N-methyl-thiocarbamoyl]urea 1, l dimethyl-2-thio-3-[ N-( 3-dimethylaminopropyl)- N-methyl-thiocarbamoyl]urea triethanolamine salt of 1,l-dimethyl-2-thio-3-[(4- methylpiperazinl -yl )-thiocarbony1]urea Synthesis of the Compounds The compounds of Formulas la and lb can be prepared by the general procedure described in U.S. Pat. No. 3,166,564 and further described in J. Med. Chem. 14, 772 (1971) i.e.', by reacting an appropriate substituted thiocarbamoyl chloride with an alkali metal or ammonium thiocyanate to form the corresponding substituted thiocarbamoyl isothiocyanate and then reacting the latter with an appropriate secondary amine.

The salts of these compounds can be prepared by mixing an equimolar amount of the desired acid or an equimolar amount of the desired base with the appropriate dithiobiuret in a suitable solvent.

The following examples are given to illustrate the above-described processes. All parts are by weight unless specified otherwise.

EXAMPLE 1 Preparation of 1 l -dimethy1-2-thio-3-[(4-propylpiperazinl-y1)- thiocarbonyl]urea A solution of 12 parts of N-propylpiperazine in 50 parts of acetone was added dropwise to a solution of 14.2 parts of dimethylthiocarbamoyl isothiocyanate in 100 parts of acetone at to 15C. The solution was then allowed to warm to room temperature, stirred for approximately 2 hours, and then filtered.

The solvent was removed under vacuum and the residue dissolved in 50 parts of 10% sodium hydroxide. The aqueous solution was washed twice with 50 parts of chloroform and then acidified with glacial acetic acid to about pH 7. The acidified solution was then extracted twice with SO-part portions of methylene chloride. The hydrocarbon layers were combined, dried over anhydrous magnesium sulfate, filtered, and the solvent was then removed under reduced pressure to give 13.5 parts of l,l-dimethyl-2-thio-3-[(4- propylpiperazin-1-yl)-thiocarbonyl]-urea as a viscous oil.

EXAMPLE 2 Preparation of l,1-dimethyl-2-thio-3-[N-(Z-dimethylaminoethyl)-N- methyl-thiocarbamoyl]urea A solution of 10.2 parts of N,N,N-trimethyl ethylene diamine in 20 parts of acetone was added dropwise to 14.2 parts of dimethylthiocarbamoyl isothiocyanate in parts of acetone at l015C. The solution was allowed to warm to room temperature, stirred for an additional 2 hours, and then filtered.

The solvent was removed under reduced pressure and the residue was dissolved in a mixture of 100 parts of chloroform and 50 parts of 10% aqueous sodium hydroxide solution. This mixture was shaken and then separated. The aqueous layer was acidified to about pH 7 with glacial acetic acid and then extracted three times with 50 part portions of methylene chloride. These extracts were combined, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed therefrom under reduced pressure to give 13 parts of the crude product. Crystallization from ethanol gave 5 parts of pure l,1-dimethyl-2-thio-3-[N-(2- dimethylaminoethyl)-N-methyl-thiocarbamoyl]urea, m.p. 9394C.

EXAMPLE 3 Preparation of l, l-dimethyl-2-thio-3-[N-(3-dimethylaminopropyl)-N- methyl-thiocarbamoyl]urea A solution of 11.6 parts of N,N,N'-trimethyltrimethylenediamine in 30 parts of acetone was added dropwise to 14.2 parts of dimethylthiocarbamoyl isothiocyanate in 100 parts of acetone at 1015C. The solution was allowed to warm to room temperature and then stirred for an additional hour.

The solvent was removed under reduced pressure and the residue was recrystallized twice from ethanol to give 3.2 parts of crystalline 1,1-dimethyl-2-thio-3- [N-(3-dimethylaminopropyl-N-methylthiocarbamoyl1urea, m.p. l08-1 10C.

EXAMPLE 4 Preparation of 1,l-ciimethyl-2-thio-3-[(4-methylpiperazin-1-yl)- thiocarbonyl]urea A solution of 100 parts of N-methylpiperazine in 100 parts of acetone was added dropwise to 142 parts of dimethylthiocarbamoyl isothiocyanate in 650 parts of acetone at l0l5C. The resulting solution was allowed to warm to room temperature and stirred for 16 hours, during which time a solid precipitated. The solid acetic acid salt of l,l-dimethyl-2-thio-3-[N-(3- dimethylamino-3-methylpropyl)-N-methylthiocarbamoyl]urea acetic acid salt of l,l-dimethyl-2-thio-3-{N-[2- (pyrrolidinl -yl)- l -methylethyl]-N-methylthiocarbamoyl}urea nitric acid salt of l,l-dimethyl-2-thio-3-{N-[3- (azacycloheptl -yl l -methylpropyl]-N-methylthiocarbamoyllurea EXAMPLE 6 Preparation of the sodium salt of l, l -dimethyl-2-thio-3-[(4-propylpiperazinl -yl thiocarbonyl]urea 0.8 Part of sodium hydroxide is added to a solution of 5.5 parts of l, l -dimethyl-2-thio-3-[(4- propylpiperazin-l-yl)-thiocarbonyl]urea in 50 parts of water. The resulting mixture can be stirred until all the solid is dissolved to give an aqueous solution of the desired sodium salt of l,l-dimethyl-2-thio-3-[(4- propylpiperazinl -yl )-thiocarbonyl ]urea.

By using an appropriate base with an appropriate dithiobiuret, the following salts can be prepared similarly:

sodium salt of l,l-dimethyl-2-thio-3-[(1,2,2-

trimethylhydrazino )-thiocarbonyl ]urea sodium salt of 1,1-dimethyl-2-thio-3-[ (1,2,2-

trimethylhydrazino)-thiocarbonyl ]urea potassium salt of 1,l-dimethyl-2-thio-3-[(l-methyl- 2-ethyl-3-hexylhydrazino)-thiocarbamoyl]urea potassium salt of 1, l -dimethyl-2-thio-3-[N- (azacycloheptl -yl )-N-methyl-thiocarbamoyl]urea calcium salt of l,l-dimethyl-2-thio-3-[N-(py rolidinl-yl)-N-methyl-thiocarbamoyl]urea calcium salt of 1,1-dimethyl-2-thio-3-[l-(2- dimethylaminoethyl)-2,2-diethylhydrazinothiocarbonyl]urea zinc salt of 1, l -dimethyl-2-thio-3-[ 1-( 3- diethylaminopropyl)-2,2-dimethylhydrazinothiocarbonyl]urea zinc salt of 1,1-dimethyl-2-thio-3-[N-(pyrrolidin-lyl)-N-(Z-dimethylaminoethyl)-thiocarbamoyl]urea magnesium salt of l,l-dimethyl-2-thio-3-{N- (pyrrolidin- 1 -yl )-N-[ 2-( pyrrolidinl -yl )-ethyl]- thiocarbamoyl}urea magnesium salt of l,1-dimethyl-2-thio-3-[N,N-bis(2- dimethylaminoethyl)-thiocarbamoyl]urea manganese salt of l,l-dimethyl-2-thio-3-[N-(6- dimethylaminohexyl)-N-methylthiocarbamoyl]urea manganese salt of l,l-dimethyl-2-thio-3-[1-(2- diethylaminoethyl )-N-methyl-carbamoyl]urea copper salt of l,l-dimethyl-2-thio-3-[N,N-bis(2- diethylamino)-thiocarbamoyl]urea copper salt of l,1-dimethyl-2-thio-3-{N-[2- (pyrrolidin- 1 -yl )ethyl]-N-methyl-carbamoyl} urea tetramethyl ammonium salt of l, l-dimethyl-2-thio-3- 3 ,4,5-trimethylpiperazin-1-yl)-thiocarbonyl]urea trimethyl-n-butyl ammonium salt of l,1-dimethyl-2- thio-3-[2,4,6-trimethylpiperazin-1-yl)- thiocarbonyl]urea tetra-n-butyl ammonium salt of l,l-dimethyl-2-thio- 3-[(2,4,5-trimethylpiperazin-l-yl)- thiocarbonyl]urea trimethyl-n-dodecyl ammonium salt of 1,1-dimethyl- 2-thio-3-[ 2,6-dimethyl-4-isopropylpiperazinl yl)-thiocarbonyl]urea tetraethyl ammonium salt of l,l-dimethyl-2-thio-3- [(3-methyl-l,3-diazacyclopent-l-yl)- thiocarbonyl]urea trimethyl benzyl ammonium salt of l,l-dimethyl-2- thio-3-[ 3-pentyll ,3-diazacyclopentl -yl thiocarbonyl]urea tri-n-butyl benzyl ammonium salt of l,l-dimethyl-2- thio-3-[(4-isopropylpiperazin-1-yl)- thiocarbonyl]urea lithium salt of l, l-dimethyl-2-thio-3-[ (4- ethylpiperazinl -yl )-thiocarbonyl ]urea EXAMPLE 7 Preparation of the triethanolamine salt of l, l-dimethyl-2-thio-3-[(4-methylpiperazinl -yl thiocarbonyl]urea Three parts of triethanolamine is added dropwise to a slurry of 5 parts of l,l-dimethyl-2-thio-3-[(4- methylpiperazin-l-yl)-thiocarbonyl]urea in 40 parts of water at room temperature. The resulting slightly cloudy yellow solution is then filtered to remove impurities thereby affording 48 parts of a 17% aqueous solution of the triethanolamine salt of l,l-dimethyl-2-thio- 3-[(4-methylpiperazinl -yl )-thiocarbonyl urea.

Similarly, by use of the appropriate amine and dithiobiuret the following salts can be prepared:

ammonia salt of l l -dimethyl-2-thio-3-[ 4- methylpiperazinl -yl )-thiocarbonyl]urea methylamine salt of l,1-dimethyl-2-thio-3-[(4- ethylpiperazinl -yl )-thiocarbonyl ]urea dibutylamine salt of l,l-dimethyl-2-thio-3-[(4- propylpiperazinl -yl )-thiocarbonyl ]urea dibutanolamine salt of l,l-dimethyl-2-thio-3-[N-(2- dimethylaminoethyl)-N-methylthiocarbamoyl]urea hydrazine salt of 1,1-dimethyl-2-thio-3-[N-(2- dimethylaminoethyl)-N-methylthiocarbamoyl urea N,N-dimethylhydrazine salt of 1,1-dimethyl-2-thio-3- [N-(Z-dimethylaminopropyl)-N-methylthiocarbamoyl1urea methylhydrazine salt of l,l-dimethyl-2-thio-3-[N-(2- dimethylaminopropyl)'N-methylthiocarbamoyl1urea morpholine salt of l,l-dimethyl-2-thio-3-[(4- methylpiperazinl-yl )-thiocarbonyl]urea piperadine salt of l,l-dimethyl-2-thio-3-[(4- methylpiperazinl -yl )-thiocarbonyl urea hexamethyleneimine salt of l,l-dimethyl-2-thio-3- [(4-methylpiperazinl -yl )-thiocarbonyl]urea dodecylamine salt of l,l-dimethyl-2-thio-3-[N-(2- dimethylaminoethyl)-N-methylthiocarbamoyl1urea pyrrolidine salt of 1,l-dimethyl-2-thio-3-[N-(2- dimethylaminoethyl)-N-methylthiocarbamoyl1urea benzylamine salt of l,l-dimethyl-2-thio-3-[N-(2- dimethylaminopropyl)-N-methylthiocarbamoyl urea trimethylamine salt of l,l-dimethyl-2-thio-3-[N-(2- dimethylaminopropyl)-N-methylthiocarbamoyl urea The use of the compounds of the present invention as miticides is the subject matter of copending US. patent application Ser. No. 358,396 filed simultaneously herewith by Colin L. McIntosh. A complete description of formulations and methods of application of these compounds is contained therein and is hereby incorporated herein by reference.

Use of the Compounds as Intermediates No. 304,793, filed Nov. 8, 1972.

What is claimed is: 1. A compound of the formula.

H C s H s C-C n l u NCN-C-N N-R H3C c c Wherein R is alkyl of 1 to 6 carbon atoms or salts of these compounds with acids or bases, the acids being selected from those having an ionization constant of at least 1X10 and the salts formed with bases containing the cation selected from Li*, Na, K*', Ca Cu Zn, Mg, Mn, and

where R R and R are the same or different and represent hydrogen, Alkyl of 1 through 4 carbon atoms or hydroxyl alkyl of 2 through 4 carbon atoms; R, is hydrogen, alkyl of 1 through 12 carbon atoms, benzyl, amino, methylamino, or dimethyl amino; R and R taken together to form a ring that is (CH O-(CH or -(CH where j is 4-6 and R6 and R are H.

2. Compound of claim 1 which is hydrobromic acid salt of l,l-dimethyl-2-thio-3-[(4methylpiperazin-lyl)-thiocarbonyl]urea.

3. Compound of claim 1 which is l,l-dimethyl-2- thio-3-[(4-propylpiperazin-l-yl)-thiocarbonyl]urea.

4. Compound of claim 1 which is 1,1-dimethyl-2- thio-3-[ (4-methylpiperazinl -yl )-thiocarbonyl]urea 5. Compound of claim 1 which is the sodium salt of l,1-dimethyl-2-thio-3-[(4-methylpiperazin-1-yl)- thiocarbonyl]urea.

6. Compound of claim 1 which is the triethanolamine salt of 1,l-dimethyl-2-thio-3-[(4-methylpiperazin-lyl)-thiocarbonyl]urea. 

1. A COMPOUND OF THE FORMULA.
 2. Compound of claim 1 which is hydrobromic acid salt of 1,1-dimethyl-2-thio-3-((4-methylpiperazin-1-yl)-thiocarbonyl)urea.
 3. Compound of claim 1 which is 1,1-dimethyl-2-thiO-3-((4-propylpiperazin-1-yl)-thiocarbonyl)urea.
 4. Compound of claim 1 which is 1,1-dimethyl-2-thio-3-((4-methylpiperazin-1-yl)-thiocarbonyl)urea
 5. Compound of claim 1 which is the sodium salt of 1,1-dimethyl-2-thio-3-((4-methylpiperazin-1-yl)-thiocarbonyl)urea.
 6. Compound of claim 1 which is the triethanolamine salt of 1,1-dimethyl-2-thio-3-((4-methylpiperazin-1-yl)-thiocarbonyl)urea. 